System Organ Class (SOC) and Adverse Reaction

n

%

BLOOD AND LYMPHATIC SYSTEM DISORDERS

anemia*

54

2.1

leukopenia and neutropenia*

44

1.7

lymphadenopathy*

35

1.3

CARDIAC DISORDERS

atherosclerosis such as myocardial infarction*

10

0.4

atrioventricular block*

3

0.1

tricuspid valve incompetence*

3

0.1

EAR AND LABYRINTH DISORDERS

vertigo*

7

0.3

tinnitus

6

0.2

ENDOCRINE DISORDERS

hypogonadism*

16

0.81

EYE DISORDERS

visual impairment*

8

0.3

GASTROINTESTINAL DISORDERS

diarrhea*

510

19.5

nausea

269

10.3

vomiting*

177

6.8

abdominal pain (upper and lower)*

160

6.1

gastroenteritis and colitis*

66

2.5

dyspepsia

53

2

pancreatitis*

45

1.7

Gastroesophageal Reflux Disease (GERD)*

40

1.5

hemorrhoids

39

1.5

flatulence

36

1.4

abdominal distension

34

1.3

constipation*

26

1

stomatitis and oral ulcers*

24

0.9

duodenitis and gastritis*

20

0.8

gastrointestinal hemorrhage including rectal hemorrhage*

13

0.5

dry mouth

9

0.3

gastrointestinal ulcer*

6

0.2

fecal incontinence

5

0.2

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

fatigue including asthenia*

198

7.6

HEPATOBILIARY DISORDERS

hepatitis including AST, ALT, and GGT increases*

91

3.5

hepatomegaly

5

0.2

cholangitis

3

0.1

hepatic steatosis

3

0.1

IMMUNE SYSTEM DISORDERS

hypersensitivity including urticaria and angioedema*

70

2.7

immune reconstitution syndrome

3

0.1

INFECTIONS AND INFESTATIONS

upper respiratory tract infection*

363

13.9

lower respiratory tract infection*

202

7.7

skin infections including cellulitis, folliculitis, and furuncle*

86

3.3

METABOLISM AND NUTRITION DISORDERS

hypercholesterolemia*

192

7.4

hypertriglyceridemia*

161

6.2

weight decreased*

61

2.3

decreased appetite

52

2

blood glucose disorders including diabetes mellitus*

30

1.1

weight increased*

20

0.8

lactic acidosis*

11

0.4

increased appetite

5

0.2

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

musculoskeletal pain including arthralgia and back pain*

166

6.4

myalgia*

46

1.8

muscle disorders such as weakness and spasms*

34

1.3

rhabdomyolysis*

18

0.7

osteonecrosis

3

0.1

NERVOUS SYSTEM DISORDERS

headache including migraine*

165

6.3

insomnia*

99

3.8

neuropathy and peripheral neuropathy*

51

2

dizziness*

45

1.7

ageusia*

19

0.7

convulsion*

9

0.3

tremor*

9

0.3

cerebral vascular event*

6

0.2

PSYCHIATRIC DISORDERS

anxiety*

101

3.9

abnormal dreams*

19

0.7

libido decreased

19

0.7

RENAL AND URINARY DISORDERS

renal failure*

31

1.2

hematuria*

20

0.8

nephritis*

3

0.1

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

erectile dysfunction*

34

1.71

menstrual disorders - amenorrhea, menorrhagia*

10

1.72

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

rash including maculopapular rash*

99

3.8

lipodystrophy acquired including facial wasting*

58

2.2

dermatitis/rash including eczema and seborrheic dermatitis*

50

1.9

night sweats*

42

1.6

pruritus*

29

1.1

alopecia

10

0.4

capillaritis and vasculitis*

3

0.1

VASCULAR DISORDERS

hypertension*

47

1.8

deep vein thrombosis*

17

0.7

*Represents a medical concept including several similar MedDRA PTs
1 Percentage of male population (N=2,038)
2 Percentage of female population (N=574)

Study 863
(48 Weeks)

Study 720
(360 Weeks)

Study 730
(48 Weeks)

Variable

Limit****1

Lopinavir and Ritonavir 400/100 mg Twice Daily + d4T + 3TC
(N = 326)

Nelfinavir
750 mg Three Times Daily + d4T + 3TC
(N = 327)

Lopinavir and Ritonavir Twice Daily + d4T + 3TC
(N = 100)

Lopinavir and Ritonavir Once Daily
+ TDF + FTC (N=333)

Lopinavir and Ritonavir Twice Daily + TDF +FTC (N=331)

Chemistry

High

Glucose

250 mg/dL

2%

2%

4%

0%

<1%

Uric Acid

12 mg/dL

2%

2%

5%

<1%

1%

SGOT/ AST2

180 U/L

2%

4%

10%

1%

2%

SGPT/ ALT2

215 U/L

4%

4%

11%

1%

1%

GGT

300 U/L

N/A

N/A

10%

N/A

N/A

Total Cholesterol

300 mg/dL

9%

5%

27%

4%

3%

Triglycerides

750 mg/dL

9%

1%

29%

3%

6%

Amylase

2 x ULN

3%

2%

4%

N/A

N/A

Lipase

2 x ULN

N/A

N/A

N/A

3%

5%

Chemistry

Low

Calculated Creatinine Clearance

<50 mL/min

N/A

N/A

N/A

2%

2%

Hematology

Low

Neutrophils

<0.75 x 109/L

1%

3%

5%

2%

1%

1 ULN = upper limit of the normal range; N/A = Not Applicable.
2 Criterion for Study 730 was >5x ULN (AST/ALT).

Study 888
(48 Weeks)

Study 9572 and Study 765****3
(84 to 144
Weeks)

Study 802
(48 Weeks)

Variable

Limit****1

Lopinavir and Ritonavir 400/100 mg Twice Daily + NVP + NRTIs (N = 148)

Investigator- Selected Protease Inhibitor(s) + NVP + NRTIs (N = 140)

Lopinavir and Ritonavir Twice Daily
+ NNRTI +
NRTIs
(N = 127)

Lopinavir and Ritonavir
800/200 mg Once Daily
+ NRTIs (N=300)

Lopinavir and Ritonavir 400/100 mg Twice Daily
+ NRTIs (N=299)

Chemistry

High

Glucose

250 mg/dL

1%

2%

5%

2%

2%

Total Bilirubin

3.48 mg/dL

1%

3%

1%

1%

1%

SGOT/AST4

180 U/L

5%

11%

8%

3%

2%

SGPT/ALT4

215 U/L

6%

13%

10%

2%

2%

GGT

300 U/L

N/A

N/A

29%

N/A

N/A

Total Cholesterol

300 mg/dL

20%

21%

39%

6%

7%

Triglycerides

750 mg/dL

25%

21%

36%

5%

6%

Amylase

2 x ULN

4%

8%

8%

4%

4%

Lipase

2 x ULN

N/A

N/A

N/A

4%

1%

Creatine Phosphokinase

4 x ULN

N/A

N/A

N/A

4%

5%

Chemistry

Low

Calculated Creatinine Clearance

<50 mL/min

N/A

N/A

N/A

3%

3%

Inorganic Phosphorus

<1.5 mg/dL

1%

0%

2%

1%

<1%

Hematology

Low

Neutrophils

<0.75 x 109/L

1%

2%

4%

3%

4%

Hemoglobin

<80 g/L

1%

1%

1%

1%

2%

1 ULN = upper limit of the normal range; N/A = Not Applicable.
2 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 29) or 533/133 mg twice daily (n = 28) for 84 weeks. Patients received lopinavir and ritonavir in combination with NRTIs and efavirenz.
3 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 36) or 400/200 mg twice daily (n = 34) for 144 weeks. Patients received lopinavir and ritonavir in combination with NRTIs and nevirapine.
4 Criterion for Study 802 was >5x ULN (AST/ALT).

Variable

Limit****1

Lopinavir and Ritonavir Twice Daily + RTIs
(N = 100)

Chemistry

High

Sodium

149 mEq/L

3%

Total Bilirubin

≥ 3.0 x ULN

3%

SGOT/AST

180 U/L

8%

SGPT/ALT

215 U/L

7%

Total Cholesterol

300 mg/dL

3%

Amylase

2.5 x ULN

7%2

Chemistry

Low

Sodium

< 130 mEq/L

3%

Hematology

Low

Platelet Count

< 50 x 109/L

4%

Neutrophils

< 0.40 x 109/L

2%

1 ULN = upper limit of the normal range.
2 Subjects with Grade 3 to 4 amylase confirmed by elevations in pancreatic amylase.

Concomitant Drug Class:
Drug Name

Effect on Concentration of Lopinavir or Concomitant Drug

Clinical Comments

HIV-1 Antiviral Agents

HIV-1 Protease Inhibitor: fosamprenavir/ritonavir

↓ amprenavir
↓ lopinavir

An increased rate of adverse reactions has been observed with co- administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.

HIV-1 Protease Inhibitor: indinavir*

↑ indinavir

Decrease indinavir dose to 600 mg twice daily, when co-administered with lopinavir and ritonavir 400/100 mg twice daily. Lopinavir and ritonavir once daily has not been studied in combination with indinavir.

HIV-1 Protease Inhibitor: nelfinavir*

↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir

Lopinavir and ritonavir once daily in combination with nelfinavir is not recommended [see Dosage and Administration (2)].

HIV-1 Protease Inhibitor: ritonavir*

↑ lopinavir

Appropriate doses of additional ritonavir in combination with lopinavir and ritonavir with respect to safety and efficacy have not been established.

HIV-1 Protease Inhibitor: saquinavir

↑ saquinavir

The saquinavir dose is 1,000 mg twice daily, when co-administered with lopinavir and ritonavir 400/100 mg twice daily. Lopinavir and ritonavir once daily has not been studied in combination with saquinavir.

HIV-1 Protease Inhibitor: tipranavir*

↓ lopinavir

Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.

HIV CCR5 – Antagonist: maraviroc*

↑ maraviroc

When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.

Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*,
nevirapine*

↓ lopinavir

Increase the dose of lopinavir and ritonavir tablets to 500/125 mg when lopinavir and ritonavir tablet is co-administered with efavirenz or nevirapine. Lopinavir and ritonavir once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration (2)].

Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine

↑ lopinavir

Appropriate doses of the combination with respect to safety and efficacy have not been established.

Nucleoside Reverse Transcriptase Inhibitor: didanosine

Lopinavir and ritonavir tablets can be administered simultaneously with didanosine without food.

For lopinavir and ritonavir oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after lopinavir and ritonavir oral solution (given with food).

Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate*

↑ tenofovir

Patients receiving lopinavir and ritonavir and tenofovir should be monitored for adverse reactions associated with tenofovir.

Nucleoside Reverse Transcriptase Inhibitors: abacavir
zidovudine

↓ abacavir
↓ zidovudine

The clinical significance of this potential interaction is unknown.

Other Agents

Alpha 1- Adrenoreceptor
Antagonist:
alfuzosin

↑ alfuzosin

Contraindicated due to potential hypotension [see Contraindications (4)].

Antianginal:
ranolazine

↑ ranolazine

Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)].

Antiarrhythmics:
dronedarone

↑ dronedarone

Contraindicated due to potential for cardiac arrhythmias [see Contraindications (4)].

Antiarrhythmics e.g. amiodarone,
bepridil,
lidocaine (systemic),
quinidine

↑ antiarrhythmics

Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with lopinavir and ritonavir.

Anticancer Agents:
abemaciclib,
apalutamide,
encorafenib,
ibrutinib,
ivosidenib,
dasatinib,
neratinib,
nilotinib,
venetoclax,
vinblastine,
vincristine

↑ anticancer agents
↓lopinavir/ritonavir#

Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors [see Contraindications (4)].

Avoid co-administration of encorafenib or ivosidenib with lopinavir and ritonavir due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with lopinavir and ritonavir cannot be avoided, modify dose as recommended in encorafenib USPI. If co- administration of ivosidenib with lopinavir and ritonavir cannot be avoided, reduce ivosidenib dose to 250 mg once daily.

Avoid use of neratinib, venetoclax or ibrutinib with lopinavir and ritonavir.

For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir and ritonavir is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as lopinavir and ritonavir. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Anticoagulants:
warfarin,
rivaroxaban

↑↓ warfarin

↑ rivaroxaban

Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during lopinavir and ritonavir and warfarin co-administration is recommended.

Avoid concomitant use of rivaroxaban and lopinavir and ritonavir. Co- administration of lopinavir and ritonavir and rivaroxaban may lead to increased risk of bleeding.

Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin

↓ lopinavir
↓ phenytoin

Lopinavir and ritonavir may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.

Lopinavir and ritonavir once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended.

In addition, co-administration of phenytoin and lopinavir and ritonavir may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with lopinavir and ritonavir.

Anticonvulsants: lamotrigine,
valproate

↓ lamotrigine
↓ or ↔ valproate

A dose increase of lamotrigine or valproate may be needed when co-administered with lopinavir and ritonavir and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.

Antidepressant: bupropion

↓ bupropion
↓ active metabolite,
hydroxybupropion

Patients receiving lopinavir and ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

Antidepressant: trazodone

↑ trazodone

Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.

Anti-infective: clarithromycin

↑ clarithromycin

For patients with renal impairment, adjust clarithromycin dose as follows:

• For patients on lopinavir and ritonavir with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
• For patients on lopinavir and ritonavir with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.

Antifungals: ketoconazole*, itraconazole, voriconazole isavuconazonium sulfate*

↑ ketoconazole
↑ itraconazole
↓ voriconazole
↑ isavuconazonium

High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.

The coadministration of voriconazole and lopinavir and ritonavir should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Isavuconazonium and lopinavir and ritonavir should be coadministered with caution. Alternative antifungal therapies should be considered in these patients.

Anti-gout: colchicine

↑ colchicine

Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4)].
For patients with normal renal or hepatic function:

Treatment of gout flares-co-administration of colchicine in patients on lopinavir and ritonavir:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout flares-co-administration of colchicine in patients on lopinavir and ritonavir:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on lopinavir and ritonavir:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Antimycobacterial:
rifampin

↓ lopinavir

Contraindicated due to potential loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors or other co-administered antiretroviral agents [see Contraindications (4)].

Antimycobacterial: bedaquiline

↑ bedaquiline

Bedaquiline should only be used with lopinavir and ritonavirif the benefit of co-administration outweighs the risk.

Antimycobacterial: rifabutin*

↑ rifabutin and rifabutin metabolite

Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.

Antiparasitic: atovaquone

↓ atovaquone

Clinical significance is unknown; however, increase in atovaquone doses may be needed.

Antipsychotics:
lurasidone

pimozide

↑ lurasidone

↑ pimozide

Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)].

Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac
arrhythmias [see Contraindications (4)].

Antipsychotics: quetiapine

↑ quetiapine

Initiation of lopinavir and ritonavir in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
Initiation of quetiapine in patients taking lopinavir and ritonavir:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

Contraceptive:
ethinyl estradiol*

↓ ethinyl estradiol

Because contraceptive steroid concentrations may be altered when lopinavir and ritonavir is co- administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.

Dihydropyridine Calcium
Channel Blockers: e.g.
felodipine,
nifedipine,
nicardipine

↑ dihydropyridine
calcium channel
blockers

Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered.

Disulfiram/metronidazole

Lopinavir and ritonavir oral solution contains ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Endothelin Receptor Antagonists: bosentan

↑ bosentan

Co-administration of bosentan in patients on lopinavir and ritonavir:
In patients who have been receiving lopinavir and ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of lopinavir and ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of lopinavir and ritonavir.
After at least 10 days following the initiation of lopinavir and ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Ergot Derivatives:
dihydroergotamine,
ergotamine,
methylergonovine

↑ ergot derivatives

Contraindicated due to potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)].

GI Motility Agent:
cisapride

↑ cisapride

Contraindicated due to potential for cardiac arrhythmias [see Contraindications (4)].

GnRH Receptor Antagonists: elagolix

↑ elagolix
↓ lopinavir/ritonavir

Concomitant use of elagolix 200 mg twice daily and lopinavir and ritonavir for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and lopinavir and ritonavir to 6 months.

Hepatitis C direct acting antiviral: elbasvir/grazoprevir

↑ elbasvir/grazoprevir

Contraindicated due to increased risk of alanine transaminase (ALT) elevations [see Contraindications (4)].

Hepatitis C direct acting antivirals:
boceprevir*
glecaprevir/Pibrentasvir

simeprevir

sofosbuvir/velpatasvir/voxilaprevi
r

ombitasvir/paritaprevir/ ritonavir and dasabuvir*

↓ lopinavir
↓ boceprevir
↓ ritonavir
↑ glecaprevir
↑ pibrentasvir
↑ simeprevir

↑ sofosbuvir
↑ velpatasvir
↑ voxilaprevir
↑ ombitasvir
↑ paritaprevir
↑ ritonavir
↔ dasabuvir

It is not recommended to co-administer lopinavir and ritonavir and boceprevir, glecaprevir/pibrentasvir, simeprevir, sofosbuvir/velpatasvir/voxilaprevir,or ombitasvir/paritaprevir/ritonavir and dasabuvir.

Herbal Products:
St. John's Wort (hypericum
perforatum)

↓ lopinavir

Contraindicated due to potential for loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors [see Contraindications (4)].

Lipid-modifying agents

HMG-CoA Reductase Inhibitors:
lovastatin
simvastatin

atorvastatin
rosuvastatin

Microsomal triglyceride transfer
protein (MTTP) Inhibitor:
lomitapide

↑ lovastatin
↑ simvastatin

↑ atorvastatin
↑ rosuvastatin

↑ lomitapide

Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4)].

Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.

Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the
exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold.
Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications (4)].

Immunosuppressants: e.g.
cyclosporine,
tacrolimus,
sirolimus

↑ immunosuppressants

Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with lopinavir and ritonavir.

Kinase Inhibitors:
fostamatinib (also see anticancer agents above)

↑ fostamatinib
metabolite R406

Monitor for toxicities of R406 such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.

Long-acting beta-adrenoceptor Agonist:
salmeterol

↑ salmeterol

Concurrent administration of salmeterol and lopinavir and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Narcotic Analgesics: methadone,*
fentanyl

↓ methadone
↑ fentanyl

Dosage of methadone may need to be increased when co-administered with lopinavir and ritonavir.

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with lopinavir and ritonavir.

PDE5 inhibitors: avanafil,
sildenafil,
tadalafil,
vardenafil

↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil

Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio®) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications(4)].

Do not use lopinavir and ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving lopinavir and ritonavir. Co-administration of lopinavir and ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio®) is contraindicated [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with lopinavir and ritonavir:
Co-administration of ADCIRCA in patients on lopinavir and ritonavir:
In patients receiving lopinavir and ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of lopinavir and ritonavir in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of lopinavir and ritonavir. Stop ADCIRCA at least 24 hours prior to starting lopinavir and ritonavir. After at least one week following the initiation of lopinavir and ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:

• Sildenafil: 25 mg every 48 hours
• Tadalafil: 10 mg every 72 hours
• Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.

Sedative/Hypnotics:
triazolam,
orally administered midazolam

↑ triazolam
↑ midazolam

Contraindicated due to potential for prolonged or increased sedation or respiratory depression
[see Contraindications (4)].

Sedative/Hypnotics:
parenterally administered midazolam

↑ midazolam

If lopinavir and ritonavir is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.

Systemic/Inhaled/
Nasal/Ophthalmic
Corticosteroids: e.g.,
betamethasone
budesonide
ciclesonide
dexamethasone
fluticasone
methylprednisolone
mometasone
prednisone
triamcinolone

↓ lopinavir

↑ glucocorticoids

Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids.

Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.

• see Clinical Pharmacology (12.3)for magnitude of interaction.

refers to interaction with apalutamide.